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Yu M, Zhang K, Wang S. High expression levels of S1PR3 and PDGFRB indicates unfavorable clinical outcomes in colon adenocarcinoma. Heliyon 2024; 10:e35532. [PMID: 39170287 PMCID: PMC11336742 DOI: 10.1016/j.heliyon.2024.e35532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/20/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
Background Studies verified that sphingosine kinase 1 (SPHK1)/sphingosine 1-phosphate receptors (S1PRs) and platelet-derived growth factor receptors (PDGFRs) play important roles in tumor occurrence and progression. However, the expression and clinical value of SPHK1/S1PRs and PDGFRs in colon adenocarcinoma (COAD) remains unclear. This study aimed to explore the expression of SPHK1/S1PRs and PDGFRs in COAD and further investigate their roles in predicting the prognosis of patients with COAD. Methods SPHK1/S1PRs and PDGFRs expression in tissues from patient with COAD were analyzed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Kaplan-Meier survival analysis was used to evaluate the prognostic roles of SPHK1/S1PRs and PDGFRs in patients with COAD. Spearman's correlation analysis was performed to assess the relationship between SPHK1/S1PRs and PDGFRs in COAD. Then, χ2 test was performed to analyze the correlation between SPHK1/S1PR3/PDGFRB and clinicopathological characteristics of the patients. Additionally, possible signaling pathways co-regulated by S1PR3 and PDGFRB were predicted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to identify hub genes that co-regulated S1PR3 and PDGFRB expression. A prognostic model based on hub genes was constructed for patients with COPD. Finally, the relationship between the hub genes and tumor immune cell infiltration was investigated. Results The expression levels of SPHK1 and PDGFRB were significantly upregulated in COAD patient tissues (P < 0.001 and P < 0.001, respectively). Moreover, Kaplan-Meier analysis showed that patients with COAD with high expression levels of SPHK1 and S1PR3 had shorter overall survival (OS) than those with low expression levels (P = 0.013 and P = 0.005, respectively). Spearman's correlation analysis verified a strong positive correlation (P < 0.001, r = 0.790) between the expression of S1PR3 and PDGFRB. In addition, we found that high SPHK1 and PDGGRB expression levels were associated with perineural invasion (P < 0.001 and P = 0.011, respectively). High expression of S1PR3 and PDGGRB was prominently associated with N stage (P = 0.002 and P = 0.021, respectively). High levels of SPHK1, S1PR3, and PDGFRB were associated with lymph node invasion. (P = 0.018, P = 0.004, and P = 0.001, respectively). GO and KEGG results revealed that S1PR3 and PDGFRB may participate in COAD cell extracellular matrix organization and cellular signal transduction. Five hub genes, SFRP2, GPRC5B, RSPO3, FGF14, and TCF7L1, were identified using LASSO regression. Survival analysis showed that the OS in the high-risk group was remarkably shorter than that in the low-risk group. The results indicated that tumor immune cells were significantly increased in the high-risk group compared to those in the low-risk group. Conclusions S1PR3 and PDGFRB may be important markers for predicting lymphatic metastasis and poor prognosis in patients with COAD. The underlying mechanisms may involve immune cell infiltration.
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Affiliation(s)
- Mengsi Yu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Kainan Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Clinical Laboratory, The People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Song Wang
- Department of Ophthalmology, General Hospital of Xinjiang Military Command, Urumqi, China
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Mohammed S, Bindu A, Viswanathan A, Harikumar KB. Sphingosine 1-phosphate signaling during infection and immunity. Prog Lipid Res 2023; 92:101251. [PMID: 37633365 DOI: 10.1016/j.plipres.2023.101251] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/28/2023]
Abstract
Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.
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Affiliation(s)
- Sabira Mohammed
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India
| | - Anu Bindu
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India
| | - Arun Viswanathan
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India; Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India.
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3
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Miao YD, Quan WX, Dong X, Gan J, Ji CF, Wang JT, Zhang F. Prognosis-related metabolic genes in the development of colorectal cancer progress and perspective. Gene 2023; 862:147263. [PMID: 36758843 DOI: 10.1016/j.gene.2023.147263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023]
Abstract
Colorectal cancer (CRC) is one of the most commonplace malignant tumors in the world. The occurrence and development of CRC are involved in numerous events. Metabolic reprogramming is one of the hallmarks of cancer and is convoluted and associated with carcinogenesis. Lots of metabolic genes are involved in the occurrence and progression of CRC. Study methods combining tumor genomics and metabolomics are more likely to explore this field in depth. In this mini-review, we make the latest progress and future prospects into the different molecular mechanisms of seven prognosis-related metabolic genes, we screened out in previous research, involved in the occurrence and development of CRC.
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Affiliation(s)
- Yan-Dong Miao
- The Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Wu-Xia Quan
- Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Xin Dong
- The Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Jian Gan
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Cui-Feng Ji
- Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Jiang-Tao Wang
- Department of Thyroid and Breast Surgery, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China
| | - Fang Zhang
- The Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China.
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4
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Clinical relevance of CERK and SPHK1 in breast cancer and their association with metastasis and drug resistance. Sci Rep 2022; 12:18239. [PMID: 36309544 PMCID: PMC9617946 DOI: 10.1038/s41598-022-20976-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/21/2022] [Indexed: 12/31/2022] Open
Abstract
Despite numerous reports on the altered sphingolipids metabolism in human cancers, their clinical significance in breast cancer remains obscure. Previously, we identified the high levels of sphingolipids, ceramide phosphates and sphingosine phosphates, and the genes involved in their synthesis, CERK and SPHK1, in breast cancer patients. The present study aimed to determine the correlations of CERK and SPHK1 with clinical outcomes as well as metastasis and drug resistance markers. Both local and TCGA cohorts were analysed. High-confidence regulatory interaction network was constructed to find association of target genes with metastasis and drug resistance. Furthermore, correlations of CERK and SPHK1 with selected metastasis and drug resistance markers were validated in both cohorts. Overexpression of CERK and SPHK1 was associated with nodal metastasis, late tumor stage and high proliferation potency. In addition, increased CERK expression was also indicative of poor patient survival. Computational network analysis revealed the association of CERK and SPHK1 with known metastasis markers MMP-2 and MMP-9 and drug resistance markers ABCC1 and ABCG2. Correlation analysis confirmed the associations of target genes with these markers in both local as well as TCGA cohort. The above findings suggest clinical utility of CERK and SPHK1 as potential biomarkers in breast cancer patients and thus could provide novel leads in the development of therapeutics.
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Petrusca DN, Mulcrone PL, Macar DA, Bishop RT, Berdyshev E, Suvannasankha A, Anderson JL, Sun Q, Auron PE, Galson DL, Roodman GD. GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival. Cancers (Basel) 2022; 14:cancers14030772. [PMID: 35159039 PMCID: PMC8833953 DOI: 10.3390/cancers14030772] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary New therapies have greatly improved the progression-free and overall survival for patients with “standard risk” multiple myeloma (MM). However, patients with “high risk” MM, in particular patients whose MM cells harbor non-functional p53, have very short survival times because of the early relapse and rapid development of highly therapy-resistant MM. In this report, we identify a novel mechanism responsible for Growth Factor Independence-1 (GFI1) regulation of the growth and survival of MM cells through its modulation of sphingolipid metabolism, regardless of their p53 status. We identify the Sphingosine-1-Phosphate Phosphatase (SGPP1) gene as a novel direct target of GFI1 transcriptional repression in MM cells, thus increasing intracellular sphingosine-1-phosphate levels, which stabilizes c-Myc. Our results support GFI1 as an attractive therapeutic target for all types of MM, including the “high risk” patient population with non-functional p53, as well as a possible therapeutic approach for other types of cancers expressing high levels of c-Myc. Abstract Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5’ end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.
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Affiliation(s)
- Daniela N. Petrusca
- Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA; (P.L.M.); (A.S.); (J.L.A.); (G.D.R.)
- Correspondence: ; Tel.: +1-(317)-278-5548
| | - Patrick L. Mulcrone
- Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA; (P.L.M.); (A.S.); (J.L.A.); (G.D.R.)
| | - David A. Macar
- Department of Biological Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15219, USA; (D.A.M.); (P.E.A.)
| | - Ryan T. Bishop
- Department of Tumor Biology, H. Lee Moffitt Cancer Research Center and Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA;
| | - Evgeny Berdyshev
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA;
| | - Attaya Suvannasankha
- Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA; (P.L.M.); (A.S.); (J.L.A.); (G.D.R.)
- Richard L. Rodebush Veterans Affairs Medical Center, 1481 W 10th St., Indianapolis, IN 46202, USA
| | - Judith L. Anderson
- Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA; (P.L.M.); (A.S.); (J.L.A.); (G.D.R.)
| | - Quanhong Sun
- Department of Medicine, Division of Hematology/Oncology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, UPMC Hillman Cancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA; (Q.S.); (D.L.G.)
| | - Philip E. Auron
- Department of Biological Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15219, USA; (D.A.M.); (P.E.A.)
| | - Deborah L. Galson
- Department of Medicine, Division of Hematology/Oncology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, UPMC Hillman Cancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA; (Q.S.); (D.L.G.)
| | - G. David Roodman
- Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, 980 Walnut St., Indianapolis, IN 46202, USA; (P.L.M.); (A.S.); (J.L.A.); (G.D.R.)
- Richard L. Rodebush Veterans Affairs Medical Center, 1481 W 10th St., Indianapolis, IN 46202, USA
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6
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Engin AB, Engin A. Indoleamine 2,3-Dioxygenase Activity-Induced Acceleration of Tumor Growth, and Protein Kinases-Related Novel Therapeutics Regimens. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:339-356. [PMID: 33539022 DOI: 10.1007/978-3-030-49844-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Indoleamine 2,3-dioxygenase (IDO) is overexpressed in response to interferon-gamma (IFN-γ). IDO-mediated degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway by immune cells is associated with the anti-microbial, and anti-tumor defense mechanisms. In contrast, IDO is constitutively expressed by various tumors and creates an immunosuppressive microenvironment around the tumor tissue both by depletion of the essential amino acid Trp and by formation of Kyn, which is immunosuppressive metabolite of Trp. IDO may activate its own expression in human cancer cells via an autocrine aryl hydrocarbon receptor (AhR)- interleukin 6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) signaling loop. Although IDO is not a unique marker, in many clinical trials serum IDO activity is suggested to be an important parameter in the pathogenesis of cancer development and growth. Measuring IDO activity in serum seems to be an indicator of cancer growth rate, however, it is controversial whether this approach can be used as a reliable guide in cancer patients treated with IDO inhibitors. Thus, IDO immunostaining is strongly recommended for the identification of higher IDO producing tumors, and IDO inhibitors should be included in post-operative complementary therapy in IDO positive cancer cases only. Novel therapies that target the IDO pathway cover checkpoint protein kinases related combination regimens. Currently, multi-modal therapies combining IDO inhibitors and checkpoint kinase blockers in addition to T regulatory (Treg) cell-modifying treatments seem promising.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
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Velazquez FN, Hernandez-Corbacho M, Trayssac M, Stith JL, Bonica J, Jean B, Pulkoski-Gross MJ, Carroll BL, Salama MF, Hannun YA, Snider AJ. Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid. Cell Signal 2020; 79:109875. [PMID: 33290840 PMCID: PMC8244749 DOI: 10.1016/j.cellsig.2020.109875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina M. Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
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Affiliation(s)
- Fabiola N Velazquez
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Hernandez-Corbacho
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Magali Trayssac
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jeffrey L Stith
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph Bonica
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Bernandie Jean
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Michael J Pulkoski-Gross
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Brittany L Carroll
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Mohamed F Salama
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Ashley J Snider
- Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
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Roy S, Mohammad T, Gupta P, Dahiya R, Parveen S, Luqman S, Hasan GM, Hassan MI. Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer. ACS OMEGA 2020; 5:21550-21560. [PMID: 32905276 PMCID: PMC7469376 DOI: 10.1021/acsomega.0c02165] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 08/10/2020] [Indexed: 06/11/2023]
Abstract
The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.
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Affiliation(s)
- Sonam Roy
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Taj Mohammad
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Preeti Gupta
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Rashmi Dahiya
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Shahnaz Parveen
- Molecular
Bioprospection Department, CSIR-Central
Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Molecular
Bioprospection Department, CSIR-Central
Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Gulam Mustafa Hasan
- Department
of Biochemistry, College of Medicine, Prince
Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Kingdom of Saudi Arabia
| | - Md. Imtaiyaz Hassan
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
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Park SB, Choi BI, Lee BJ, Kim NJ, Jeong YA, Joo MK, Kim HJ, Park JJ, Kim JS, Noh YS, Lee HJ. Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation. Dig Dis Sci 2020; 65:2284-2293. [PMID: 31776862 DOI: 10.1007/s10620-019-05971-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/16/2019] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. METHODS We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). RESULTS CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation. CONCLUSIONS Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.
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Affiliation(s)
- Seung Bin Park
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Byung-Il Choi
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Beom Jae Lee
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea.
| | - Nam Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Yoon A Jeong
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Moon Kyung Joo
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Hyo Jung Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Jong-Jae Park
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Jae Seon Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea
| | - Yoon-Seok Noh
- College of Pharmacy, Chungbuk National University, Cheongju, Korea
| | - Hyun Joo Lee
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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10
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Grbčić P, Sedić M. Sphingosine 1-Phosphate Signaling and Metabolism in Chemoprevention and Chemoresistance in Colon Cancer. Molecules 2020; 25:E2436. [PMID: 32456134 PMCID: PMC7287727 DOI: 10.3390/molecules25102436] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.
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Affiliation(s)
| | - Mirela Sedić
- Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia;
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11
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Acharya S, Yao J, Li P, Zhang C, Lowery FJ, Zhang Q, Guo H, Qu J, Yang F, Wistuba II, Piwnica-Worms H, Sahin AA, Yu D. Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer. Cancer Res 2019; 79:4211-4226. [PMID: 31239273 DOI: 10.1158/0008-5472.can-18-3803] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 04/16/2019] [Accepted: 06/19/2019] [Indexed: 12/28/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasis-promoting gene FSCN1 via NFκB activation. Activation of the SPHK1/NFκB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFκB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFκB, as promising therapeutic targets in TNBC. SIGNIFICANCE: SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFκB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.
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Affiliation(s)
- Sunil Acharya
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Cancer Biology Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas
| | - Jun Yao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ping Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Chenyu Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Frank J Lowery
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Cancer Biology Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas
| | - Qingling Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hua Guo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jingkun Qu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fei Yang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Helen Piwnica-Worms
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aysegul A Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Cancer Biology Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas
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12
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Wang J, Feng W, Li F, Shi W, Zhai C, Li S, Zhu Y, Yan X, Wang Q, Liu L, Xie X, Li M. SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms. Pulm Circ 2018; 9:2045894018816977. [PMID: 30430898 PMCID: PMC6295694 DOI: 10.1177/2045894018816977] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension.
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Affiliation(s)
- Jian Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Wei Feng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Fangwei Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Wenhua Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Cui Zhai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Shaojun Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Yanting Zhu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Xin Yan
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Qingting Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Lu Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Xinming Xie
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Manxiang Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
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13
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Liu SQ, Xu CY, Wu WH, Fu ZH, He SW, Qin MB, Huang JA. Sphingosine kinase 1 promotes the metastasis of colorectal cancer by inducing the epithelial‑mesenchymal transition mediated by the FAK/AKT/MMPs axis. Int J Oncol 2018; 54:41-52. [PMID: 30365116 PMCID: PMC6254930 DOI: 10.3892/ijo.2018.4607] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 10/01/2018] [Indexed: 12/21/2022] Open
Abstract
It was demonstrated that Sphingosine kinase 1 (SphK1) promotes tumor progression and confers the malignancy phenotype of colorectal cancer by activating the focal adhesion kinase (FAK) pathway. However, further clarification is required to determine if SphK1 promotes the metastasis of colorectal cancer by inducing epithelial‑mesenchymal transition (EMT), and its mechanisms have not been fully elucidated. Immunohistochemistry staining was used to detect protein expression in normal colonic mucosa tissues and colorectal cancer tissues. Cells were transfected to overexpress SphK1, downregulate SphK1 or downregulate FAK. An MTT assay was used to detect the drug toxicity to cells. Transwell and wound healing assays were used to detect cell migration ability. Reverse transcription‑polymerase chain reaction and western blot analysis were used to detect the expression of mRNA and protein, respectively. Scanning electron microscopy was used to observe the microvilli and pseudopodia of the cells. The analysis of protein expression in 114 human colorectal cancer tissues demonstrated that the expressions of SphK1, FAK, phosphorylated (p)‑FAK, E‑cadherin and vimentin were associated with the metastasis of colorectal cancer. Furthermore, the patients with colorectal cancer with SphK1‑positive cancer demonstrated poorer prognosis compared with SphK1‑negative cancer. FAK knockdown and SphK1 knockdown of human colon cancer RKO cells inhibited the EMT and migrational potency, along with the expression of p‑FAK, p‑protein kinase B (AKT) and matrix metalloproteinase (MMP)2/9. In contrast, SphK1 overexpression promoted EMT, migrational potency, and the expression of p‑FAK, p‑AKT and MMP2/9 in HT29 cells. Additionally, the EMT and migrational potency of SphK1‑overexpressing HT29 cells was suppressed by a FAK inhibitor, and the expression of p‑FAK, p‑AKT and MMP2/9 was suppressed by blocking the FAK pathway. In conclusion, SphK1 promoted the migration and metastasis of colon cancer by inducing EMT mediated by the FAK/AKT/MMPs axis.
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Affiliation(s)
- Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Chun-Yan Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Wen-Hong Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Zhen-Hua Fu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Si-Wei He
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Meng-Bin Qin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
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14
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Zheng X, Li W, Ren L, Liu J, Pang X, Chen X, Kang D, Wang J, Du G. The sphingosine kinase-1/sphingosine-1-phosphate axis in cancer: Potential target for anticancer therapy. Pharmacol Ther 2018; 195:85-99. [PMID: 30347210 DOI: 10.1016/j.pharmthera.2018.10.011] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate (S1P), play many important roles in cellular activities. Ceramide and sphingosine inhibit cell proliferation and induce cell apoptosis while S1P has the opposite effect. Maintaining a metabolic balance of sphingolipids is essential for growth and development of cells. Sphingosine kinase (SPHK) is an important regulator for keeping this balance. It controls the level of S1P and plays important roles in proliferation, migration, and invasion of cancer cells and tumor angiogenesis. There are two isoenzymes of sphingosine kinase, SPHK1 and SPHK2. SPHK1 is ubiquitously expressed in most cancers where it promotes survival and proliferation, while SPHK2 is restricted to only certain tissues and its functions are not well characterized. SPHK1 is currently considered as a novel target for the treatment of cancers. Targeting SPHK1 would provide new strategies for cancer treatment and improve the prognosis of cancer patients. Here we review and summarize the current research findings on the SPHK1-S1P axis in cancer from many aspects including structure, expression, regulation, mechanism, and potential inhibitors.
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Affiliation(s)
- Xiangjin Zheng
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Wan Li
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Liwen Ren
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Jinyi Liu
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Xiaocong Pang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - De Kang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Jinhua Wang
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
| | - Guanhua Du
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
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15
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Cai XD, Che L, Lin JX, Huang S, Li J, Liu XY, Pan XF, Wang QQ, Chen L, Lin MJ, Huang ZH, Ma HM, Wu Y, Liu SM, Zhou YB. Krüppel-like factor 17 inhibits urokinase plasminogen activator gene expression to suppress cell invasion through the Src/p38/ MAPK signaling pathway in human lung adenocarcionma. Oncotarget 2018; 8:38743-38754. [PMID: 28454121 PMCID: PMC5503568 DOI: 10.18632/oncotarget.17020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/30/2017] [Indexed: 11/25/2022] Open
Abstract
Krüppel-like factor 17 (KLF17) has been reported to be involved in invasion and metastasis suppression in lung cancer, but the molecular mechanisms underlying the anti-invasion and anti-metastasis roles of KLF17 in lung cancer are not fully illustrated. Here, we showed that KLF17 inhibited the invasion of A549 and H322 cells; the anti-invasion effect of KLF17 was associated with the suppression of urokinase plasminogen activator (uPA/PLAU) expression. KLF17 can bind with the promoter of uPA and inhibit its expression. Enforced expression of uPA abrogated the anti-invasion effect of KLF17 in A549 and H322 cells. In addition, immunohistochemistry staining showed that the protein expression of KLF17 was negatively correlated with that of uPA in archived samples from patients with lymph node metastasis of lung adenocarcinoma (rho = −0.62, P = 0.01). The mutually exclusive expression of KLF17 with uPA could predict lymph node metastasis for lung adenocarcinoma (AUC = 0.758, P = 0.005). Enforced expression of KLF17 inhibited the expression of phosphorylated Src and phosphorylated p38/MAPK in A549 and H322 cells. The invasiveness of the cells were suppressed by treating with sb203580 (p38/MAPK inhibitor) or HY-13805 (PP2, Src inhibitor). furthermore, p38/MAPK inhibition could block the KLF17-induced reduction of p-p38/MAPK and uPA, and Src inhibition enhanced the KLF17-induced suppression of p-Src and uPA in A549 and H322 cells. In conclusion, our study indicated that KLF17 suppressed the uPA-mediated invasion of lung adenocarcinoma. The Src and p38/MAPK signaling pathways were suggested as mediators of KLF17-induced uPA inhibition, thus providing evidence that KLF17 might be a potential anti-invasion candidate for lung adenocarcinoma.
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Affiliation(s)
- Xing-Dong Cai
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Li Che
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Jia-Xin Lin
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Shuai Huang
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Jiong Li
- Department of Anatomy, The Medical College of Jinan University, Guangzhou 510630, China
| | - Xiao-Yan Liu
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Xing-Fei Pan
- Department of Infectious Disease, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Qin-Qin Wang
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Li Chen
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Ming-Juan Lin
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Zhi-Hong Huang
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Hong-Ming Ma
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Yi Wu
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Sheng-Ming Liu
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Yan-Bin Zhou
- Department of Pulmonary Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
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16
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Xu C, Zhang W, Liu S, Wu W, Qin M, Huang J. Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells. Oncol Lett 2018; 15:9719-9724. [PMID: 29928348 PMCID: PMC6004663 DOI: 10.3892/ol.2018.8588] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 03/16/2018] [Indexed: 12/22/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) is a master kinase that catalyzes the synthesis of sphingosine 1 phosphate and participates in the regulation of cell proliferation and autophagy. The present study aimed to assess the effects of the activation of the SphK1/extracellular signal-regulated kinase (ERK)/phosphorylated (p-)ERK pathway in the regulation of autophagy in colon cancer (HT-29) cells. Inverted fluorescence microscopy was used to detect the expression of green fluorescent protein (GFP) in the SphK1-overexpressing HT-29 cells [SphK1(+)-HT-29] and the negative control HT-29 cells (NC-HT-29). Western blotting was used to detect the protein expression levels of SphK1, ERK1/2, p-ERK1/2, as well as those of the autophagy-associated markers LC3A, ATG5, and ULK1. Protein localization and expression of the LC3A antibody were detected by immunofluorescence. The results demonstrated that GFP was similarly expressed in SphK1(+)-HT-29 and NC-HT-29 cells. However, significantly increased SphK1 mRNA and protein expression levels were detected in SphK1(+)-HT-29 cells compared with in NC-HT-29 cells, which resulted in upregulated ERK/p-ERK. Furthermore, the protein expression levels of the three autophagy-associated markers increased. LC3A protein was localized in the cytoplasm of SphK1(+)-HT-29 cells, indicating autophagy. In summary, the findings of the present study suggested that activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer HT-29 cells.
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Affiliation(s)
- Chunyan Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Wenlu Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shiquan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Wenhong Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Mengbin Qin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Jiean Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
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"Dicing and Splicing" Sphingosine Kinase and Relevance to Cancer. Int J Mol Sci 2017; 18:ijms18091891. [PMID: 28869494 PMCID: PMC5618540 DOI: 10.3390/ijms18091891] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 08/29/2017] [Accepted: 08/29/2017] [Indexed: 02/06/2023] Open
Abstract
Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or “non-oncogenic addiction”. Here we discuss additional theories of SphK cellular mislocation and aberrant “dicing and splicing” as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics.
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18
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Hatoum D, Haddadi N, Lin Y, Nassif NT, McGowan EM. Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget. Oncotarget 2017; 8:36898-36929. [PMID: 28415564 PMCID: PMC5482707 DOI: 10.18632/oncotarget.16370] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 03/02/2017] [Indexed: 12/16/2022] Open
Abstract
The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.
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Affiliation(s)
- Diana Hatoum
- School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
| | - Nahal Haddadi
- School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
| | - Yiguang Lin
- School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
| | - Najah T. Nassif
- School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
| | - Eileen M. McGowan
- School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia
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19
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Cai H, Xie X, Ji L, Ruan X, Zheng Z. Sphingosine kinase 1: A novel independent prognosis biomarker in hepatocellular carcinoma. Oncol Lett 2017; 13:2316-2322. [PMID: 28454397 PMCID: PMC5403457 DOI: 10.3892/ol.2017.5732] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 12/16/2016] [Indexed: 02/07/2023] Open
Abstract
Sphingosine kinase 1 (Sphk1) is an oncogenic kinase that is responsible for the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P). Mounting evidence suggests that Sphk1 serves a crucial role in the proliferation and development of a variety of human cancer cells. However, the role of Sphk1 in hepatocellular carcinoma (HCC) has not been fully elucidated. Therefore, the expression of Sphk1 was examined in 127 formalin-fixed, paraffin-embedded HCC tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. As a result, the expression of Sphk1 in HCC tissue was revealed to be significantly higher than in normal tissue (P<0.01). In addition, Sphk1 expression was significantly associated with tumor size, tumor stage and histological differentiation (all P<0.05). The patients with low Sphk1 expression had higher overall survival and recurrence-free survival rates compared with patients with high Sphk1 expression. Furthermore, Sphk1-specific shRNA was used to downregulate the expression of Sphk1 in HCC cell lines, including hepatoblastoma G2 and HCC-9724. The CRISPR/Cas9 based transcription activation system was used to upregulate Sphk1 expression in the normal live cell, L02. Cell proliferation, mRNA expression and protein expression were measured using Cell Counting Kit-8, reverse transcription polymerase chain reaction and western blot analysis in the transfected cells. To the best of our knowledge, the present study provides the first evidence that Sphk1 promotes HCC cell proliferation and is involved in tumor progression. Notably, the data presented suggest that Sphk1 may be a potential independent prognosis biomarker for the treatment of HCC.
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Affiliation(s)
- Huajie Cai
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xuemeng Xie
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ling Ji
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaojiao Ruan
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhihai Zheng
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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20
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Chai Y, Xu J, Yan B. The anti-metastatic effect of baicalein on colorectal cancer. Oncol Rep 2017; 37:2317-2323. [DOI: 10.3892/or.2017.5437] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 12/14/2016] [Indexed: 11/06/2022] Open
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21
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Qin M, Zhang J, Xu C, Peng P, Tan L, Liu S, Huang J. Knockdown of NIK and IKKβ-Binding Protein (NIBP) Reduces Colorectal Cancer Metastasis through Down-Regulation of the Canonical NF-κΒ Signaling Pathway and Suppression of MAPK Signaling Mediated through ERK and JNK. PLoS One 2017; 12:e0170595. [PMID: 28125661 PMCID: PMC5268490 DOI: 10.1371/journal.pone.0170595] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/06/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Despite the identification of many signaling pathways involved in colorectal cancer (CRC) tumorigenesis, metastatic CRC still remains one of the major causes of cancer related death. NIK and IKKβ-binding protein (NIBP) is one of the key regulators of the NF-κB signaling pathway, which has been implicated in CRC metastasis. The aim of this study was to investigate the possible role of NIBP in CRC metastasis through its regulation of NF-κΒ and extracellular regulated kinase/c-Janus kinase (ERK/JNK) signaling pathways. METHODS In this study NIBP, phosphorylated (p)-p65, p-ERK1/2, and p-JNK1/2 expression was examined in 130 CRC, and 25 adenoma tissue samples were studied by immunohistochemistry. NIBP shRNA knockdown was performed in HCT116 cells, and NF-κB and ERK/JNK pathway activity was measured after TNF-α stimulation in vitro and in vivo. RESULTS We found that NIBP, p-p65, p-ERK1/2, and p-JNK1/2 expression was higher in late stages of CRC compared to early stages or adenomas. Expression of p-p65, p-IκBα, p-IκBβ, p-ERK1/2, and p-JNK1/2 was inhibited in TNF-α stimulated HCT116 cells following NIBP knockdown. Nevertheless, p-ERK1/2 expression in un-transfected and NIBP knockdown HCT116 cells remained the same in the absence of TNF-α stimulation. Furthermore, cell motility and invasion were reduced in HCT116 cells following NIBP knockdown even after TNF-α treatment. Finally, primary tumor weight and liver metastasis were reduced in nude mice with orthotopically transplanted NIBP knockdown of HCT116 cells. CONCLUSION In conclusion, we demonstrated that NIBP knockdown reduces colorectal cancer metastasis through down-regulation of canonical NF-κΒ signaling and suppression of ERK and JNK signaling.
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Affiliation(s)
- Mengbin Qin
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Jinxiu Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Chunyan Xu
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Peng Peng
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Lin Tan
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Shiquan Liu
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Jiean Huang
- Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
- * E-mail:
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22
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Sánchez DI, González-Fernández B, San-Miguel B, de Urbina JO, Crespo I, González-Gallego J, Tuñón MJ. Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1-phosphate signaling pathway in a mouse model of diethylnitrosamine-induced hepatocellular carcinoma. J Pineal Res 2017; 62. [PMID: 27696512 DOI: 10.1111/jpi.12369] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/27/2016] [Indexed: 02/06/2023]
Abstract
The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma, but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p. beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Melatonin alleviated the distortion of normal hepatic architecture, lowered the incidence of preneoplastic/neoplastic lesions, and inhibited the expression of proliferative/cell cycle regulatory proteins (Ki67, PCNA, cyclin D1, cyclin E, CDK4, and CDK6). S1P levels and expression of SphK1, SphK2, and S1P receptors (S1PR1/S1PR3) were significantly elevated in DEN-treated mice. However, there was a decreased expression of S1P lyase. These effects were significantly abrogated in a time- and dose-dependent manner by melatonin, which also increased S1PR2 expression. Following DEN treatment, mice exhibited increased phosphorylation of PI3K, AKT, mTOR, STAT3, ERK, and p38, and a higher expression of NF-κB p50 and p65 subunits. Melatonin administration significantly inhibited those changes. Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the protective effects of melatonin in hepatocarcinogenesis.
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Affiliation(s)
- Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | | | | | - Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María J Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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23
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Zhou Y, Han Y, Zhang Z, Shi Z, Zhou L, Liu X, Jia X. MicroRNA-124 upregulation inhibits proliferation and invasion of osteosarcoma cells by targeting sphingosine kinase 1. Hum Cell 2016; 30:30-40. [PMID: 27743351 DOI: 10.1007/s13577-016-0148-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/04/2016] [Indexed: 12/11/2022]
Abstract
Increasing evidence has confirmed that the dysregulation of microRNAs (miRNAs) contributes to the proliferation and invasion of human cancers. Previous studies have shown that the dysregulation of miR-124 is in numerous cancers. However, the roles of miR-124 in human osteosarcoma (OS) have not been well clarified. Therefore, this study was to investigate the biological functions and molecular mechanisms of miR-124 in OS cell lines, discussing whether it could be a therapeutic biomarker of OS in the future. In this study, our results demonstrated that miR-124 was down-regulated in OS cell lines and tissues. Furthermore, the low level of miR-124 was associated with increased expression of Sphingosine kinase 1 (SPHK1) in OS cells and tissues. Up-regulation of miR-124 significantly inhibited cell proliferation, invasion, and MMP-2 and -9 expressions of OS cells. Bioinformatics analysis predicted that the SPHK1 was a potential target of miR-124. Further study by luciferase reporter assay demonstrated that miR-124 could directly target SPHK1. Overexpression of SPHK1 in OS cells transfected with miR-124 mimic partially reversed the inhibitory of miR-124. In conclusion, miR-124 inhibited cell proliferation and invasion in OS cells by downregulation of SPHK1, and that downregulation of SPHK1 was essential for the miR-124-inhibited cell invasion and in OS cells.
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Affiliation(s)
- Yan Zhou
- Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China
| | - Yanzhen Han
- Department of General Surgery V, Affiliated Hospital of Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China.
| | - Zhitao Zhang
- Laboratory Medicine, Sixth Hospital of Handan, Handan, 056000, Hebei, People's Republic of China
| | - Zhe Shi
- Department of General Surgery V, Affiliated Hospital of Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China
| | - Liyuan Zhou
- Department of General Surgery V, Affiliated Hospital of Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China
| | - Xiaohong Liu
- Department of General Surgery V, Affiliated Hospital of Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China
| | - Xiaoyan Jia
- Department of General Surgery V, Affiliated Hospital of Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China
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24
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Mikuła-Pietrasik J, Sosińska P, Maksin K, Kucińska MG, Piotrowska H, Murias M, Woźniak A, Szpurek D, Książek K. Colorectal cancer-promoting activity of the senescent peritoneal mesothelium. Oncotarget 2016; 6:29178-95. [PMID: 26284488 PMCID: PMC4745719 DOI: 10.18632/oncotarget.4932] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 07/24/2015] [Indexed: 02/03/2023] Open
Abstract
Gastrointestinal cancers metastasize into the peritoneal cavity in a process controlled by peritoneal mesothelial cells (HPMCs). In this paper we examined if senescent HPMCs can intensify the progression of colorectal (SW480) and pancreatic (PSN-1) cancers in vitro and in vivo. Experiments showed that senescent HPMCs stimulate proliferation, migration and invasion of SW480 cells, and migration of PSN-1 cells. When SW480 cells were injected i.p. with senescent HPMCs, the dynamics of tumor formation and vascularization were increased. When xenografts were generated using PSN-1 cells, senescent HPMCs failed to favor their growth. SW480 cells subjected to senescent HPMCs displayed up-regulated expression of transcripts for various pro-cancerogenic agents as well as increased secretion of their products. Moreover, they underwent an epithelial-mesenchymal transition in the Smad 2/3-Snail1-related pathway. The search for mediators of senescent HPMC activity showed that increased SW480 cell proliferation was stimulated by IL-6, migration by CXCL8 and CCL2, invasion by IL-6, MMP-3 and uPA, and epithelial-mesenchymal transition by TGF-β1. Secretion of these agents by senescent HPMCs was increased in an NF-κB- and p38 MAPK-dependent mechanism. Collectively, our findings indicate that in the peritoneum senescent HPMCs may create a metastatic niche in which critical aspects of cancer progression become intensified.
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Affiliation(s)
| | - Patrycja Sosińska
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Konstantin Maksin
- Department of Clinical Pathology, Poznań University of Medical Sciences, PoznaÅń, Poland
| | - Mał Gorzata Kucińska
- Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland
| | - Hanna Piotrowska
- Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland
| | - Marek Murias
- Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland
| | - Aldona Woźniak
- Department of Clinical Pathology, Poznań University of Medical Sciences, PoznaÅń, Poland
| | - Dariusz Szpurek
- Division of Gynecological Surgery, Poznań University of Medical Sciences, Poznań, Poland
| | - Krzysztof Książek
- Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
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25
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Ye S, Mao B, Yang L, Fu W, Hou J. Thrombosis recanalization by paeoniflorin through the upregulation of urokinase‑type plasminogen activator via the MAPK signaling pathway. Mol Med Rep 2016; 13:4593-8. [PMID: 27082639 PMCID: PMC4878539 DOI: 10.3892/mmr.2016.5146] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 04/06/2016] [Indexed: 02/02/2023] Open
Abstract
Paeoniflorin, the major component of Paeonia lactiflora pall, has previously been reported to prevent thrombosis. Plasminogen activator urokinase (uPA) is a serine protease that markedly facilitates normal thrombosis resolution. Paeoniflorin and uPA have been linked to the mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, the influence of paeoniflorin on the expression of uPA was investigated and the underlying regulatory mechanism was preliminarily determined. The prothrombotic state of the model animals treated with paeoniflorin were assessed by enzyme-linked immunosorbent assay (ELISA). Additionally, the cytotoxicity of paeoniflorin on human umbilical vein endothelial cell (HUVEC) cultures was estimated using a methyl thiazolyl tetrazolium assay and the possible pathways involved in the interaction between paeoniflorin and uPA were evaluated using western blot analysis. The ELISA results demonstrated that the levels of 6-keto prostaglandin F1a, fibronectin and uPA were significantly upregulated by treatment with paeoniflorin compared with control (P<0.05). By contrast, the expression of fibrinogen, D-dimer and thromboxane B2 were inhibited. With an increase in the concentration of paeoniflorin the cell viability of HUVECs decreased gradually. The results of western blot analysis demonstrated that paeoniflorin increased the phosphorylation of MAPK 14 (p38) and MAPK 8 (JNK). The present study demonstrated that paeoniflorin has the potential to improve the prethrombotic state and recanalize thrombosis by increasing the expression of uPA, which may be mediated via regulation of the p38 and JNK MAPK signaling pathways. However, this treatment effect was dependent on the concentration of paeoniflorin used, an unsuitable concentration of the agent would result in a negative effect on the anti-thrombosis pathways.
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Affiliation(s)
- Songshan Ye
- Department of Medical Experimental Center, Zhang Zhongjing Traditional Chinese Medicine College, Nanyang Institute of Technology, Nanyang, Henan 473004, P.R. China
| | - Bingyu Mao
- Department of Medical Experimental Center, Zhang Zhongjing Traditional Chinese Medicine College, Nanyang Institute of Technology, Nanyang, Henan 473004, P.R. China
| | - Lei Yang
- Department of Medical Experimental Center, Zhang Zhongjing Traditional Chinese Medicine College, Nanyang Institute of Technology, Nanyang, Henan 473004, P.R. China
| | - Weiyun Fu
- Department of Medical Experimental Center, Zhang Zhongjing Traditional Chinese Medicine College, Nanyang Institute of Technology, Nanyang, Henan 473004, P.R. China
| | - Junran Hou
- Department of Medical Experimental Center, Zhang Zhongjing Traditional Chinese Medicine College, Nanyang Institute of Technology, Nanyang, Henan 473004, P.R. China
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26
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Zhao LP, Xu TM, Kan MJ, Xiao YC, Cui MH. A novel uPAg-KPI fusion protein inhibits the growth and invasion of human ovarian cancer cells in vitro. Int J Mol Med 2016; 37:1310-6. [PMID: 27035617 PMCID: PMC4829131 DOI: 10.3892/ijmm.2016.2540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 03/17/2016] [Indexed: 12/19/2022] Open
Abstract
Urokinase-type plasminogen activator (uPA) acts by breaking down the basement membrane and is involved in cell proliferation, migration and invasion. These actions are mediated by binding to the uPA receptor (uPAR) via its growth factor domain (GFD). The present study evaluated the effects of uPAg-KPI, a fusion protein of uPA-GFD and a kunitz protease inhibitor (KPI) domain that is present in the amyloid β-protein precursor. Using SKOV-3 cells, an ovarian cancer cell line, we examined cell viability, migration, invasion and also protein expression. Furthermore, we examined wound healing, and migration and invasion using a Transwell assay. Our data showed that uPAg-KPI treatment reduced the viability of ovarian cancer SKOV-3 cells in both a concentration and time-dependent manner by arresting tumor cells at G1/G0 phase of the cell cycle. The IC50 of uPAg-KPI was 0.5 µg/µl after 48 h treatment. At this concentration, uPAg-KPI also inhibited tumor cell colony formation, wound closure, as well as cell migration and invasion capacity. At the protein level, western blot analysis demonstrated that uPAg-KPI exerted no significant effect on the expression of total extracellular signal-regulated kinase (ERK)1/ERK2 and AKT, whereas it suppressed levels of phosphorylated ERK1/ERK2 and AKT. Thus, we suggest that this novel uPAg-KPI fusion protein reduced cell viability, colony formation, wound healing and the invasive ability of human ovarian cancer SKOV-3 cells in vitro by regulating ERK and AKT signaling. Further studies using other cell lines will confirm these findings.
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Affiliation(s)
- Li-Ping Zhao
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Tian-Min Xu
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Mu-Jie Kan
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ye-Chen Xiao
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Man-Hua Cui
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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27
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Liu Y, An S, Ward R, Yang Y, Guo XX, Li W, Xu TR. G protein-coupled receptors as promising cancer targets. Cancer Lett 2016; 376:226-39. [PMID: 27000991 DOI: 10.1016/j.canlet.2016.03.031] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/14/2016] [Accepted: 03/14/2016] [Indexed: 02/07/2023]
Abstract
G protein-coupled receptors (GPCRs) regulate an array of fundamental biological processes, such as growth, metabolism and homeostasis. Specifically, GPCRs are involved in cancer initiation and progression. However, compared with the involvement of the epidermal growth factor receptor in cancer, that of GPCRs have been largely ignored. Recent findings have implicated many GPCRs in tumorigenesis, tumor progression, invasion and metastasis. Moreover, GPCRs contribute to the establishment and maintenance of a microenvironment which is permissive for tumor formation and growth, including effects upon surrounding blood vessels, signaling molecules and the extracellular matrix. Thus, GPCRs are considered to be among the most useful drug targets against many solid cancers. Development of selective ligands targeting GPCRs may provide novel and effective treatment strategies against cancer and some anticancer compounds are now in clinical trials. Here, we focus on tumor related GPCRs, such as G protein-coupled receptor 30, the lysophosphatidic acid receptor, angiotensin receptors 1 and 2, the sphingosine 1-phosphate receptors and gastrin releasing peptide receptor. We also summarize their tissue distributions, activation and roles in tumorigenesis and discuss the potential use of GPCR agonists and antagonists in cancer therapy.
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Affiliation(s)
- Ying Liu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Su An
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Richard Ward
- Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom
| | - Yang Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Xiao-Xi Guo
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
| | - Wei Li
- Kidney Cancer Research, Diagnosis and Translational Technology Center of Yunnan Province, Department of Urology, The People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
| | - Tian-Rui Xu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
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28
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Overexpression of SphK1 enhances cell proliferation and invasion in triple-negative breast cancer via the PI3K/AKT signaling pathway. Tumour Biol 2016; 37:10587-93. [PMID: 26857281 DOI: 10.1007/s13277-016-4954-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/02/2016] [Indexed: 12/15/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) expression is elevated in various cancers and is associated with shorter survival times for patients. However, the molecular mechanism of SphK1 up-regulation in triple-negative breast cancer (TNBC) remains unclear. In this study, we assayed the expression level of SphK1 in TNBC tissues by qRT-PCR and immunohistochemistry. The level of S1P was quantified by ELISA in the serum of TNBC patients. Our results found that the levels of SphK1 and S1P were significantly increased in TNBC patients compared with normal control. Furthermore, knockdown of SphK1 with siRNA decreased TNBC cell proliferation and inhibited cell migration/invasion. These data suggest that SphK1 has an important role in TNBC and presents an attractive therapeutic target for the treatment for TNBC.
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29
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Xu Y, Dong B, Huang J, Kong W, Xue W, Zhu Y, Zhang J, Huang Y. Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression. Oncotarget 2016; 7:3233-44. [PMID: 26673009 PMCID: PMC4823102 DOI: 10.18632/oncotarget.6564] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/21/2015] [Indexed: 01/01/2023] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, knockdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.
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Affiliation(s)
- Yunze Xu
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Baijun Dong
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiwei Huang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Wen Kong
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yu Zhu
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jin Zhang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yiran Huang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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30
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Hair Cell Loss Induced by Sphingosine and a Sphingosine Kinase Inhibitor in the Rat Cochlea. Neurotox Res 2015; 29:35-46. [DOI: 10.1007/s12640-015-9563-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 09/15/2015] [Accepted: 09/21/2015] [Indexed: 12/27/2022]
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31
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Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway. Int J Mol Sci 2015; 16:19851-67. [PMID: 26307972 PMCID: PMC4581329 DOI: 10.3390/ijms160819851] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/27/2015] [Accepted: 07/30/2015] [Indexed: 01/07/2023] Open
Abstract
Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy.
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32
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Matrine inhibits the invasive properties of human osteosarcoma cells by downregulating the ERK-NF-κB pathway. Anticancer Drugs 2015; 25:1035-43. [PMID: 24999836 DOI: 10.1097/cad.0000000000000136] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Matrine has been used in anti-inflammatory and anticancer therapies for a long time. However, the antimetastatic effect and molecular mechanism(s) of matrine on osteosarcoma are still unclear. Therefore, the aim of this study was to assess the effects of matrine and related mechanism(s) on osteosarcoma cells. In the study, we found that matrine inhibited the proliferation of osteosarcoma cells in vivo and in vitro and inhibited tumor cell metastasis in vitro at cytotoxic doses. Matrine also decreased the expression of the matrix metalloproteinases-2 and 9, decreased p50 and p65 nuclear translocation, and decreased the phosphorylated level of I-κ-B (IκB)-β. In addition, matrine reduced the phosphorylated levels of extracellular signal-regulated kinase 1/2 proteins, which regulate the invasion of poorly differentiated cancer cells. Finally, when U2OS cells were grown as xenografts in nude mice, intragastric administration of matrine induced a significant dose-dependent decrease in tumor growth. These results show the anticancer properties of matrine, which include the inhibition of invasion and proliferation of human osteosarcoma cells.
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Zhong J, Kang J, Wang X, Jiang W, Liao H, Yuan J. TAT-OSBP-1-MKK6(E), a novel TAT-fusion protein with high selectivity for human ovarian cancer, exhibits anti-tumor activity. Med Oncol 2015; 32:118. [PMID: 25782870 DOI: 10.1007/s12032-015-0495-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 01/23/2015] [Indexed: 01/12/2023]
Abstract
To improve the selectivity of TAT-fusion proteins for targeted cancer therapy, we developed a novel TAT-based target-specific fusion protein, TAT-OSBP-1-MKK6(E), and evaluated its selectivity and anti-tumor activity in vitro and in vivo. The fusion protein containing TAT-OSBP-1-MKK6(E) has three functional domains: (1) the protein transduction domain of TAT, (2) the human ovarian cancer HO8910 cell-specific binding peptide (OSBP-1) and (3) the potential anti-tumor effector domain of MKK6(E). The transduction efficiency, selectivity, cytotoxicity and apoptotic effect of TAT-OSBP-1-MKK6(E) were examined using immunofluorescence, CCK8 assay and flow cytometry. The in vivo anti-tumor efficacy and target specificity of the fusion protein were evaluated using a nude mouse model with subcutaneous xenografts of human ovarian cancer HO8910 cells. Tumor-bearing mice were divided into three treatment groups that received tail vein injections of TAT-OSBP-1-MKK6(E), TAT-OSBP-1 or normal saline. Tumor growth inhibition was determined by tumor volume, weight and morphology. The distribution and apoptotic effect of TAT-OSBP-1-MKK6(E) were assessed by immunohistochemical staining and TUNEL assays. TAT-OSBP-1-MKK6(E) can be selectively internalized into human ovarian cancer HO8910 cells, rather than normal ovarian OSE cells. In vivo, the fusion protein was mainly expressed in the tumor xenograft, but not in ovary or liver tissues. As a result, TAT-OSBP-1-MKK6(E) significantly induced growth inhibition and apoptosis of tumor cells in vitro and in vivo, with limited effects in normal cells and tissues. TAT-OSBP-1-MKK6(E) treatment can selectively target HO8910 cells in vitro and in vivo, leading to growth inhibition and apoptosis of tumor cells. As such, TAT-OSBP-1-MKK6(E) may be a potential approach for ovarian cancer target therapy.
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Affiliation(s)
- Jiali Zhong
- Department of Obstetrics and Gynecology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, People's Republic of China
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ZHU LIANGMING, WANG ZHOU, LIN YUXIA, CHEN ZHITAO, LIU HAIBO, CHEN YING, WANG NINGNING, SONG XIUE. Sphingosine kinase 1 enhances the invasion and migration of non-small cell lung cancer cells via the AKT pathway. Oncol Rep 2014; 33:1257-63. [DOI: 10.3892/or.2014.3683] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 10/03/2014] [Indexed: 11/05/2022] Open
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Tamashiro PM, Furuya H, Shimizu Y, Kawamori T. Sphingosine kinase 1 mediates head & neck squamous cell carcinoma invasion through sphingosine 1-phosphate receptor 1. Cancer Cell Int 2014; 14:76. [PMID: 25197261 PMCID: PMC4155094 DOI: 10.1186/s12935-014-0076-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 07/24/2014] [Indexed: 02/03/2023] Open
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive loco-regional invasion. Sphingosine kinase1 (SphK1), an enzyme in sphingolipid metabolism, is emerging as a key player in HNSCC pathology. The observation that SphK1 is overexpressed in all HNSCC stages and is associated with depth of tumor invasion, metastasis and clinical failure underscores the importance of SphK1 in HNSCC pathology. Still, the mechanisms underlying SphK1 regulation of invasion have not been delineated. Therefore, we sought to mechanistically describe how SphK1 regulates invasion in HNSCC. Methods Invasion assays were used to measure invasive ability of SphK1 overexpressing human tongue squamous cell carcinoma (SCC-25 cells). Western blotting, quantitative qPCR, ELISA and zymography were used to measure the effect of SphK1 and sphingosine 1-phoshate receptor 1 (S1P1) on invasion measures, MMP-2/9, E-cadherin, EGFR, IL-6/STAT3, in SCC-25 cells. Results SphK1 expression is elevated in cells with an invasive phenotype as compared to non-invasive phenotype. We show SphK1 overexpression increased EGF-induced EGFR/ERK and AKT activity, increased matrix metalloproteinase (MMP)-2/9 mRNA and reduced E-cadherin. SphK1 overexpression also increased IL-6 concentration and EGF-induced STAT3 phosphorylation, exemplifying that SphK1 modulates IL-6/STAT3 signaling. Notably, we show that S1P1 knockdown reduced IL-6/STAT3 signaling, representing another pathway by which SphK1/S1P regulates invasion. Conclusions Taken together, our data suggest that SphK1 sits at the hub of multiple key signaling cascades, all which have been implicated in the regulation of invasiveness, making SphK1 an attractive target for the development of HNSCC therapies.
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Affiliation(s)
- Paulette M Tamashiro
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA
| | - Hideki Furuya
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA ; Clinical and Translational Research Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA
| | - Yoshiko Shimizu
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA ; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96818 USA ; Clinical and Translational Research Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA
| | - Toshihiko Kawamori
- Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813 USA ; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96818 USA ; Department of Pathology, Ichinomiya Nishi Hospital, 1 Hira, Kaimei, Ichinomiya, Aichi Pref., 494-0001 Japan
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Nguyen AV, Wu YY, Lin EY. STAT3 and sphingosine-1-phosphate in inflammation-associated colorectal cancer. World J Gastroenterol 2014; 20:10279-10287. [PMID: 25132744 PMCID: PMC4130835 DOI: 10.3748/wjg.v20.i30.10279] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 03/02/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulated evidences have demonstrated that signal transducer and activator of transcription 3 (STAT3) is a critical link between inflammation and cancer. Multiple studies have indicated that persistent activation of STAT3 in epithelial/tumor cells in inflammation-associated colorectal cancer (CRC) is associated with sphingosine-1-phosphate (S1P) receptor signaling. In inflammatory response whereby interleukin (IL)-6 production is abundant, STAT3-mediated pathways were found to promote the activation of sphingosine kinases (SphK1 and SphK2) leading to the production of S1P. Reciprocally, S1P encourages the activation of STAT3 through a positive autocrine-loop signaling. The crosstalk between IL-6, STAT3 and sphingolipid regulated pathways may play an essential role in tumorigenesis and tumor progression in inflamed intestines. Therapeutics targeting both STAT3 and sphingolipid are therefore likely to contribute novel and more effective therapeutic strategies against inflammation-associated CRC.
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Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro. Mol Biol Rep 2014; 41:5157-65. [PMID: 24816639 DOI: 10.1007/s11033-014-3382-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 04/21/2014] [Indexed: 01/14/2023]
Abstract
To investigate the potential regulation of sphingosine kinase 1 (SPHK1) on the migration, invasion, and matrix metalloproteinase (MMP) expression in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were transfected control siRNA or SPHK1 siRNA. The migration and invasion of unmanipulated control, control siRNA or SPHK1 siRNA- transfected RA-FLS in vitro were measured by the transwell system. The relative levels of SPHK1, PI3K, and AKT as well as AKT phosphorylation in RA-FLS were determined by Western blot. The levels of MMP-2/9 secreted by RA-FLS were detected by ELISA. Knockdown of SPHK1 significantly inhibited the spontaneous migration and invasion of RA-FLS, accompanied by significantly reduced levels of PI3K expression and AKT phosphorylation. Similarly, treatment with LY294002, an inhibitor of the PI3K/AKT pathway, inhibited the migration and invasion of RA-FLS. Knockdown of SPHK1 and treatment with the inhibitor synergistically inhibited the migration and invasion of RA-FLS, by further reducing the levels of PI3K expression and AKT phosphorylation. In addition, knockdown of SPHK1 or treatment with LY294002 inhibited the secretion of MMP-2 and MMP-9, and both synergistically reduced the production of MMP-2 and MMP-9 in RA-FLS in vitro. Knockdown of SPHK1 expression inhibits the PI3K/AKT activation, MMP-2 and MMP-9 expression, and human RA-FLS migration and invasion in vitro. Potentially, SPHK1 may be a novel therapeutic target for RA.
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Shang RZ, Dai B, Wang DS. Role of uPA/uPAR system in tumors. Shijie Huaren Xiaohua Zazhi 2014; 22:1235-1240. [DOI: 10.11569/wcjd.v22.i9.1235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Urokinase type plasminogen activator (uPA) is a major activator of plasminogen, and uPA receptor is the specific receptor of uPA. The uPA/uPAR system regulates plasminogen activity, which participates in degradation and remodeling of the extracellular matrix (ECM), and is involved in many pathophysiological processes. In neoplasms, the activation of plasminogen into plasmin caused by the uPA/uPAR system induces the degradation of components in the basement membrane as well as in the ECM, which provides a favorable microenvironment for tumor invasion and metastasis. In addition, the uPA/uPAR system regulates tumor proliferation and angiogenesis. In this review, we will discuss the role of the uPA/uPAR system in tumors and its potential clinical implications.
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Mao YB, Liu SQ, Tan L, Zhou Q, Huang JA. EGb761 enhances cisplatin- and etoposide-induced apoptosis of human gastric cancer SGC-7901 cells. Shijie Huaren Xiaohua Zazhi 2013; 21:3330-3337. [DOI: 10.11569/wcjd.v21.i31.3330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effect of Ginkgo biloba extract (EGb761) combined with cisplatin or etoposide on cell proliferation and apoptosis in human gastric cancer cell line SGC-7901 and to explore the possible mechanisms involved.
METHODS: SGC-7901 cells were treated with EGb761, cisplatin, etoposide, or EGb761 combined with cisplatin or etoposide. Cell viability was measured by MTT assay, and apoptosis was measured by flow cytometry. The colorimetric method was used to detect the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) and the content of malondialdehyde (MDA) in cells. The protein expression of extracellular signal-regulated kinase1/2 (ERK1/2), p-ERK1/2 and nuclear transcription factor-kappa B (NF-κB) p65 was determined by Western blot.
RESULTS: Monotherapy with each of EGb761, cisplatin and etoposide significantly inhibited the growth of SGC-790l cells in a dose- and time-dependent manner. EGb761 significantly enhanced the inhibitory effect of cisplatin and etoposide on cell growth. Cells treated with EGb761 combined either cisplatin or EGb761 showed a significantly higher level of apoptosis than those treated with cisplatin or etoposide alone. Compared to the control group, the activities of SOD, GSH-Px and CAT were notably elevated (SOD: 16.57 U/mg prot ± 3.20 U/mg prot vs 25.96 U/mg prot ± 3.57 U/mg prot; CAT: 2.51 U/mg prot ± 0.32 U/mg prot vs 3.79 U/mg prot ± 0.55 U/mg prot; GSH-Px: 22.18 µmol/(min•mg) prot ± 4.36 µmol/(min•mg) prot vs 33.49 µmol/(min•mg) prot ± 5.64 µmol/(min•mg) prot; all P < 0.05) and the content of MDA was significantly decreased (2.46 nmol/mg prot ± 0.38 nmol/mg prot vs 1.42 nmol/mg prot ± 0.26 nmol/mg prot, P < 0.05) in cells treated with EGb761. The expression of ERK1/2, p-ERK1/2 and NF-κBp65 was significantly induced by cisplatin or etoposide, while EGb761 suppressed the expression of ERK1/2, p-ERK1/2 and NF-κBp65 induced by cisplatin or etoposide. The expression levels of ERK1/2, p-ERK1/2 and NF-κBp65 in the control group, cisplatin group, EGB761 + cisplatin group, etoposide group and EGB761 + etoposide group were as follows: ERK1/2: 0.496 ± 0.078, 0.831 ± 0.091, 0.521 ± 0.082, 0.816 ± 0.101, 0.489 ± 0.072; p-ERK1/2: 0.289 ± 0.032, 0.521 ± 0.068, 0.276 ± 0.049, 0.486 ± 0.087, 0.298 ± 0.053; NF-κBp65: 0.268 ± 0.038, 0.456 ± 0.08, 0.276 ± 0.052, 0.446 ± 0.076, 0.229 ± 0.056).
CONCLUSION: EGb761 enhances cisplatin- and etoposide-induced apoptosis of SGC-7901 cells possibly by enhancing cellular antioxidant capacity and suppressing the up-regulation of ERK, p-ERK and NF-κBp65 protein expression.
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Baicalein inhibits the invasion and metastatic capabilities of hepatocellular carcinoma cells via down-regulation of the ERK pathway. PLoS One 2013; 8:e72927. [PMID: 24039823 PMCID: PMC3765161 DOI: 10.1371/journal.pone.0072927] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 07/15/2013] [Indexed: 01/13/2023] Open
Abstract
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
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Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells. Oncogene 2013; 33:3364-73. [PMID: 23893239 DOI: 10.1038/onc.2013.303] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/14/2013] [Accepted: 06/18/2013] [Indexed: 12/14/2022]
Abstract
Despite progress in the understanding of the biology and genetics of melanoma, no effective treatment against this cancer is available. The adjacent microenvironment has an important role in melanoma progression. Defining the molecular signals that control the bidirectional dialog between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. Our study aimed at defining the role of sphingosine-1-phosphate (S1P) in melanoma-stroma interactions. Transcriptomic analysis of human melanoma cell lines showed increased expression of sphingosine kinase-1 (SPHK1), the enzyme that produces S1P, as compared with normal melanocytes. Such an increase was also observed by immunohistochemistry in melanoma specimens as compared with nevi, and occurred downstream of ERK activation because of BRAF or NRAS mutations. Importantly, migration of melanoma cells was not affected by changes in SPHK1 activity in tumor cells, but was stimulated by comparable modifications of S1P-metabolizing enzymes in cocultured dermal fibroblasts. Reciprocally, incubation of fibroblasts with the conditioned medium from SPHK1-expressing melanoma cells resulted in their differentiation to myofibroblasts, increased production of matrix metalloproteinases and enhanced SPHK1 expression and activity. In vivo tumorigenesis experiments showed that the lack of S1P in the microenvironment prevented the development of orthotopically injected melanoma cells. Finally, local tumor growth and dissemination were enhanced more efficiently by coinjection of wild-type skin fibroblasts than by fibroblasts from Sphk1(-/-) mice. This report is the first to document that SPHK1/S1P modulates the communication between melanoma cells and dermal fibroblasts. Altogether, our findings highlight SPHK1 as a potential therapeutic target in melanoma progression.
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